Design at the atomic level: Design of biaryloxazolidinones as potent orally active antibiotics

Zhou, Jiacheng; Bhattacharjee, Ashoke; Chen, Shili; Chen, Yi; Duffy, Erin M.; Farmer, Jay J.; Goldberg, Joel; Hanselmann, Roger; Ippolito, Joseph A.; Lou, Rongliang; Orbin, Alia; Oyelere, Ayomi; Salvino, Joe; Springer, Dane M.; Tran, Jennifer; Wang, Deping; Wu, Yusheng; Johnson, Graham

doi:10.1016/j.bmcl.2008.10.011

Cited by 59 publications

(31 citation statements)

References 3 publications

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“…Rx-01_423 and Rx-01_667 were designed using knowledge gained from atomic resolution structures of the ribosome and from computational models that enriched for specific gramnegative activity and oral bioavailability (22,56,60). Their advantages over linezolid include an expanded spectrum that may permit the empirical treatment of serious CAP, including MRSA, and activity against linezolid-resistant enterococci and pneumococci.…”

Section: Discussionmentioning

confidence: 99%

“…Rib-X (Rx) compounds and linezolid were synthesized at Rib-X Pharmaceuticals, Inc. The procedure for the synthesis of linezolid was described previously (60). Reference standards were purchased from either Alembic Ltd., Gujarat, India (azithromycin), or Sigma-Aldrich Corp. (St. Louis, MO) (penicillin G potassium salt, levofloxacin, and amoxicillin-clavulanate [Augmentin]).…”

Section: Bacterialmentioning

confidence: 99%

“…1). Analyses of the structures together with proprietary computational tools provided details of the interactions and ways to enhance or modify those interactions, allowing for a Ͼ100-fold increase in binding affinity and a significant circumvention of resistance mechanisms (22,47,56,60). In addition, we used computational models to expand the spectrum of the oxazolidinone Rx-01 series to fastidious gram-negative microbes responsible for RTIs (56).…”

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confidence: 99%

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In Vitro Activities of the Rx-01 Oxazolidinones against Hospital and Community Pathogens

Lawrence

Danese

DeVito

et al. 2008

Antimicrob Agents Chemother

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Rx-01_423 and Rx-01_667 are two members of the family of oxazolidinones that were designed using a combination of computational and medicinal chemistry and conventional biological techniques. The compounds have a two-to eightfold-improved potency over linezolid against serious gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant streptococci, and vancomycin-resistant enterococci. This enhanced potency extends to the coverage of linezolid-resistant gram-positive microbes, especially multidrug-resistant enterococci and pneumococci. Compounds from this series expand the spectrum compared with linezolid to include fastidious gram-negative organisms like Haemophilus influenzae and Moraxella catarrhalis. Like linezolid, the Rx-01 compounds are bacteriostatic against MRSA and enterococci but are generally bactericidal against S. pneumoniae and H. influenzae.

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Section: Discussionmentioning

confidence: 99%

Section: Bacterialmentioning

confidence: 99%

mentioning

confidence: 99%

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In Vitro Activities of the Rx-01 Oxazolidinones against Hospital and Community Pathogens

Lawrence

Danese

DeVito

et al. 2008

Antimicrob Agents Chemother

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“…The strategy was therefore to link the two molecules together via an adequate bridging element and make the required structural modifications on the sparsomycin side to increase potency and selectivity 41, 44. Figure 8 shows two ( 7 and 8 ) of the numerous bridged antibiotics that were synthesized on the road to radezolid and clearly shows the evolution of the western half and the bridging unit.…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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“…In the present study, we have focused our interest on radezolid (RX-1741), the first molecule brought to clinical evaluation in the subclass of biaryloxazolidinones (49,50). Biaryloxazolidinones combine into a single molecular design the most important interactions defined by sparsomycin and linezolid with the 50S subunit of the ribosome.…”

mentioning

confidence: 99%

Cellular Pharmacokinetics of the Novel Biaryloxazolidinone Radezolid in Phagocytic Cells: Studies with Macrophages and Polymorphonuclear Neutrophils

Lemaire

Tulkens

Bambeke

2010

Antimicrob Agents Chemother

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Radezolid (RX-1741) is the first biaryloxazolidinone in clinical development. It shows improved activity, including against linezolid-resistant strains. Radezolid differs from linezolid by the presence of a biaryl spacer and of a heteroaryl side chain, which increases the ionization and hydrophilicity of the molecule at physiological pH and confers to it a dibasic character. The aim of this study was to determine the accumulation and subcellular distribution of radezolid in phagocytic cells and to decipher the underlying mechanisms. In THP-1 human macrophages, J774 mouse macrophages, and human polymorphonuclear neutrophils, radezolid accumulated rapidly and reversibly (half-lives of approximately 6 min and 9 min for uptake and efflux, respectively) to reach, at equilibrium, a cellular concentration 11-fold higher than the extracellular one. This process was concentration and energy independent but pH dependent (accumulation was reduced to 20 to 30% of control values for cells in medium at a pH of <6 or in the presence of monensin, which collapses pH gradients between the extracellular and intracellular compartments). The accumulation at equilibrium was not affected by efflux pump inhibitors (verapamil and gemfibrozil) and was markedly reduced at 4°C but was further increased in medium with low serum content. Subcellular fractionation studies demonstrated a dual subcellular distribution for radezolid, with ϳ60% of the drug colocalizing to the cytosol and ϳ40% to the lysosomes, with no specific association with mitochondria. These observations are compatible with a mechanism of transmembrane diffusion of the free fraction and partial segregation of radezolid in lysosomes by proton trapping, as previously described for macrolides.

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Design at the atomic level: Design of biaryloxazolidinones as potent orally active antibiotics

Cited by 59 publications

References 3 publications

In Vitro Activities of the Rx-01 Oxazolidinones against Hospital and Community Pathogens

In Vitro Activities of the Rx-01 Oxazolidinones against Hospital and Community Pathogens

Targeting Antibiotic Resistance

Cellular Pharmacokinetics of the Novel Biaryloxazolidinone Radezolid in Phagocytic Cells: Studies with Macrophages and Polymorphonuclear Neutrophils

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